PHARMO Database Network Research Articles

Sulfamethoxazole-Trimethoprim-Induced Hyperkalemia in Hospitalized Patients Using Potassium-Sparing Drugs: An Observational Study.

The objective of this analysis is to investigate the risk of hyperkalemia in hospitalized patients using sulfamethoxazole-trimethoprim (Co-trimoxazole) and a potassium-sparing drug (potassium-sparing diuretic or renin-angiotensin system [RAS]-inhibitor). Researchers conducted a nested case control study within a cohort of hospitalized patients using a potassium-sparing diuretic and/or a RAS-inhibitor from the PHARMO Database Network. Researchers estimated the odds ratios (ORs) and 95% confidence intervals (CI) for the risk of hyperkalemia in patients receiving both Co-trimoxazole and a potassium-sparing drug compared with patients only receiving a potassium-sparing drug. Among a cohort of 25,849 patients, researchers identified 2054 cases of hyperkalemia during hospitalization in patients also using a potassium-sparing drug. Using Co-trimoxazole in addition to a potassium-sparing drug was associated with an increased risk of hyperkalemia in hospitalized patients (ORadj = 1.65, 95% CI 1.26-2.16) compared with using only a potassium-sparing drug. There was a trend of a more pronounced association between hyperkalemia and the co-use of Co-trimoxazole and potassium-sparing drugs in patients with an estimated GFR of 15-29 mL/min (ORadj = 3.15, 95% CI 1.29-7.70). The number needed to harm for hyperkalemia induced by adding Co-trimoxazole to patients receiving a potassium-sparing drug is 19.5. Using the combination of Co-trimoxazole with a potassium-sparing drug in hospitalized patients increases the risk of hyperkalemia compared with using only a potassium-sparing drug. Physicians and other prescribers should be aware of hyperkalemia and routinely monitor serum potassium levels in hospitalized patients using this combination of drugs.

Characteristics of patients initiating PCSK9i mAb following myocardial infarction and comparability of treatment groups in the Netherlands

Abstract Background The clinical benefits of lipid lowering treatment (LLT) for reducing risk of atherosclerotic cardiovascular disease (ASCVD) are well established. Recent findings support early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors monoclonal antibodies (PCSK9i mAb) to maximize clinical benefit. However, when comparing treatment effects in a real-world setting, it is important to establish comparability of treatment groups and assess and adjust for confounding. Purpose To compare clinical characteristics and LLT use in patients initiating and not initiating PCSK9i mAb within 365 days following a myocardial infarction (MI). Methods MI events occurring in patients ≥18 years between 1 April 2016 and 31 December 2020 were identified in PHARMO Database Network, a population-based network of electronic healthcare databases linking data from general practitioners, out-patient and in-patient pharmacies and hospitals in the Netherlands. The database has about 3.3 million patients, representative of the Dutch population with respect to age and sex albeit with slight over-representation of those >80 years old. Characteristics of patients were presented by treatment groups: initiating PCSK9i mAb and not initiating PCSK9i mAb within 365 days post-MI. Characteristics and LLT use in the two treatment groups was evaluated. Results Of the 28,975 MI events, 157 (0.5%) initiated a PCSK9i mAb within 365 days. Patients who initiated a PCSK9i mAb within 365 days post-MI were younger than those who did not (median age of 63 versus 69 years), more likely to have a history of ASCVD prior to the MI event (56% versus 39%) and dyslipidaemia (55% versus. 28%), while non-initiators were more likely to have diabetes mellitus, chronic kidney disease and atrial fibrillation (Table). Patients who initiated PCSK9i mAb within 365 days post-MI had higher low-density lipoprotein cholesterol levels (3.7 versus 2.9 mmol/L), higher use of ezetimibe (25% versus 4%) and high-intensity statins (15% vs 11%, Figure). Conclusions In the Netherlands, despite being at very high risk of recurrent ASCVD, based on this dataset excluding Patient Support Programs, fewer than 1% of patients initiated a PCSK9i mAb within 365 days post-MI. Further analyses are needed to reveal if these treatment groups are comparable to assess differences and uncontrolled confounders in cardiovascular outcomes in the real world.

5-year adherence to adjuvant endocrine treatment in Dutch women with early stage breast cancer: A population-based database study (2006-2016).

Hormonal receptor (HR) positive breast tumors are common. Adjuvant hormonal therapy (AHT) with tamoxifen or Aromatase Inhibitors (AIs) is beneficial depending on the stage of the tumor. Despite the fact that AHT has been shown to improve survival and recurrence, Dutch adherence rates, which were mostly dependent on Tamoxifen prescriptions until 2006, plummeted from 80% after one year to 50% after five years. Nonadherence with AHT reduces its effectiveness. This research presents more recent adherence statistics (from 2006 to 2016), on a larger sample (7,996 vs 1,451), as well as factors that influence AHT adherence. In addition to tamoxifen data, AIs are now included. As low use of adjuvant endocrine therapy is a potentially important and modifiable risk factor for poor outcome, it is important to monitor the rate as an indicator of women's burden of disease and the direction of adherence trends. The Netherlands Cancer Registry (NCR) was used to find women with early-stage breast cancer who started AHT within a year of surgery and were linked to the PHARMO Database Network (n =8,679). The Kaplan-Meier approach was used to measure AHT adherence five years after treatment was started, with a 60-day gap between refills as our primary outcome. Furthermore, the Medication Possession Rate (MPR) was determined using a cutoff of ≥80%. Analysis was performed on influential factors of adherence. The proportion of persistent women declined over time to reach 46.6% at the end of the fifth year and 53.3% of the women had a MPR ≥80% during the fifth year. Older and being diagnosed in 2006-2010 were associated with AHT adherence. Dutch 5-year AHT adherence appears to remain poor. Improving AHT adherence in HR+ breast cancer survivors is a critical medical need.

Impact of implementing Dutch versus European guideline risk factor targets in older patients with ischaemic heart disease.

In patients with ischaemic heart disease (IHD) aged > 70years, Dutch and European guidelines recommend different treatment targets: low-density lipoprotein cholesterol (LDL-c) < 2.6versus < 1.4 mmol/l and systolic blood pressure (SBP) < 140 versus < 130 mm Hg, respectively. How this impacts cardiovascular event-free life expectancy has not been investigated. The study objective was to compare estimated lifelong treatment benefits of implementing Dutch and European LDL‑c and SBP targets. Data from patients aged 71-80years hospitalised for IHD in 2017-2019 were extracted from the PHARMO Database Network, which links primary and secondary healthcare settings, with follow-up until 31December 2020. Potential benefit according to treatment strategy (in gain in event-free years) was estimated using the SMART-REACH model. Of the 3003 eligible patients, 1186 (39%) had missing LDL‑c and/or SBP measurements. Of the 1817 included patients (36% women, median age at event: 74years (interquartile range (IQR): 72-77), 84% achieved the Dutch targets for both LDL‑c and SBP; for European targets, this was 23% and 61%, respectively. If Dutch targets were met for LDL‑c and SBP (n = 1281), the additional effect of reaching European targets was amedian gain of 0.6event-free life years (IQR: 0.3-1.0). The greatest effect could be reached in patients not reaching Dutch targets (n = 501), with amedian gain of 0.6(IQR: 0.2-1.2) and 1.7(IQR: 1.2-2.5) event-free years with Dutch versus European targets. In patients aged > 70years with IHD, implementation of European targets resulted in agreater gain of event-free years compared with Dutch targets, especially in patients with poorer risk factor control. The considerable number of patients with missing risk factor documentation suggested additional opportunities for risk reduction.

Prescribing of low-dose rivaroxaban in patients with atherosclerotic cardiovascular disease in the United Kingdom and the Netherlands.

Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users. In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers. In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1years, Netherlands -2.4years; P< .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P< .001) than nonusers. There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice.

Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands.

Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries. We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N=127,743, the Netherlands: N=2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.

Real-world data of HER2-low metastatic breast cancer: A population based cohort study

BackgroundWith the introduction of investigational human epidermal growth factor receptor 2 (HER2) targeting treatments, thorough understanding of breast cancer with different HER2 expression levels is critical. The aim of this study was to compare clinicopathologic characteristics and survival of patients with metastatic breast cancer according to the level of HER2 expression. MethodsWomen with distant metastatic breast cancer during 2008–2016 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO Database Network. Breast cancer samples were categorised as HER2 immunohistochemistry score 0 (IHC0), HER2-low or HER2+. ResultsAmong women with hormone receptor (HR) positive metastatic breast cancer (n = 989), 373 (38%) cancers were HER2 IHC0, 472 (48%) were HER2-low and 144 (15%) were HER2+. Among HR negative patients (n = 272), the proportion of HER2 IHC0, HER2-low and HER2+ was 110 (40%), 104 (38%) and 58 (21%) respectively.Within the HR + cohort, patients with HER2 IHC0 or HER2-low cancer were significantly older compared to HER2+ patients. This age difference was not seen in the HR-cohort. The localisation of distant metastases differed significantly between HER2 IHC0 or HER2-low versus HER2+ cases. Survival rates did not differ markedly by subtypes. ConclusionSubstantial proportion of patients had a HER2-low breast cancer. No clear differences in survival were found when comparing HER2 and HR status. Getting more granular insights in the level of HER2 expression and addressing HER2-low as a separate category could help to assess the impact of emerging treatment strategies. Therefore, more detailed information on HER2 expression should be routinely reported.

Treatment and low-density lipoprotein cholesterol levels in patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular risk: a population-based cross-sectional study in the Netherlands

Objective To describe treatment patterns, low-density lipoprotein cholesterol (LDL-C) levels and healthcare resource utilization (HCRU) in the Netherlands in 2018 of patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular (CV) risk. Methods From the PHARMO Database Network adult patients with a diagnosis or receiving lipid lowering therapy (LLT) between 2009 and 2018 were selected. Patients at high or very high CV risk according to 2016 ESC/EAS guidelines with recorded LDL-C levels who were treated with LLT or were characterized as statin intolerant in 2018 were included. LLT treatment patterns, LDL-C levels and HCRU (General Practitioner [GP] consultations and hospitalizations) were assessed. Results The study population included 54,346 patients, of which 70% were at very high CV risk and 30% at high CV risk. The majority (93%) received statin monotherapy, mostly of moderate (73%) or high (15%) intensity. Only 3% received a combination of statin and ezetimibe. Statin intolerance, based on a treatment algorithm, was estimated at 3%. Average LDL-C decreased with LLT intensity. Overall, 74% reached LDL-C < 2.5 mmol/l and 34% <1.8 mmol/l with their current treatment, and 46% reached their LDL-C goal according to 2016 ESC/EAS guidelines. The highest rates of hospitalizations and GP consultations, including home visits, were recorded in patients with peripheral artery disease or polyvascular disease. Conclusion The treatment of hypercholesterolaemia and mixed dyslipidaemia in patients at high or very high CV risk in the Netherlands was suboptimal in 2018. To further lower CV risk alternative treatment strategies using add-on therapies are needed.

Incidence of malignancies in patients with multiple sclerosis versus a healthy matched cohort: A population-based cohort study in the Netherlands using the PHARMO Database Network

This study estimated the incidence of malignancy in patients with multiple sclerosis (MS) versus a matched general population cohort in the Netherlands. Adults with a diagnosis of MS between 2006 and 2014 in the General Practitioner (GP) Database of the PHARMO Database Network with ≥ 1 year of patient history were matched to four non-MS individuals based on year of birth, sex, and GP practice. Patients were followed-up until the earliest malignancy diagnosis, death, or end of data collection. Age-adjusted incidence rates (IR) were measured overall and by cancer type. Standardized incidence ratios (SIR) were calculated as the ratio of stratification-specific IRs in the MS and non-MS cohorts. A total of 1,692 MS patients were matched to 6,768 non-MS patients. Age-adjusted IR of any malignancy, excluding non-melanoma skin cancer (n = 27), in the MS cohort was 48.3 (95%CI:30.1–66.5) per 10,000 PY. An increased incidence of any malignancy was observed in the MS cohort versus the non-MS cohort (SIR 1.8 [95%CI:1.1–2.5]). The most commonly observed malignancies in the MS cohort were breast cancer (n = 8; IR 20.4 [95%CI:6.3–34.5] per 10,000 PY) and melanoma (n = 6; IR 14.8 [95%CI:3.0–26.7] per 10,000 PY). The corresponding SIR observed between cohorts was 1.4 (95%CI:0.4–2.4) and 3.4 (95%CI:0.7–6.2), respectively. While the small increased incidence of malignancy in the MS cohort could be an artefact created by a different distribution of risk factors, an increased incidence of malignancy in MS patients in the Netherlands cannot be excluded.

Non-cardiovascular medication and readmission for heart failure: an observational cohort study

Background Among heart failure (HF) patients, hospital readmissions are a major concern. The medication taken by a patient may provide information on comorbidities and conditions and may be used as an indicator to identify populations at an increased risk of HF readmission. Aim This study explored the use of non-cardiovascular medication at hospital discharge from the first HF admission in search of indicators of high risk of readmission for HF. Method The study included 22,476 HF patients from the Dutch PHARMO Database Network at their first HF hospitalization. The data was divided into training and validation sets. A Cox regression model with demographics, date of first HF hospital admission and non-cardiovascular medication present at discharge, adjusted for cardiovascular medication, was developed in the training set and subsequently implemented in the validation set. Results The study included 22,476 patients, mean age 76.7years (range 18-104) and median follow-up time 2.5years (range 0-15.7years). During the study period 6,725 (29.9%) patients were readmitted for HF, with a median time-to-readmission of 7months (range 0-14.3years). Non-cardiovascular medication associated with a high risk of readmission for HF were identified as indicators of high risk, with no implied causal relationship. Patients prescribed antigout medications presented a 25% increased risk of readmission (HR 1.25, 95%CI 1.09-1.45, P = 0.002). Patients using insulin had an 18% higher risk of readmission versus patients not using insulin (HR 1.18, 95%CI 1.06-1.32, P = 0.002), but not versus patients treated with other blood-glucose-lowering drugs. No association between the risk of readmission and NSAIDs use was observed. Conclusion The results suggest that diabetes is responsible for the higher HF-readmission risk observed in patients prescribed insulin. The observed risk in users of antigout medication should be further investigated. The absence of an association with the use of NSAIDs should be interpreted with caution.

Antidepressant use during pregnancy and development of preeclampsia: A focus on classes of action and specific transporters/receptors targeted by antidepressants

ObjectiveThe association between antidepressants and preeclampsia has been inconsistently reported. Given the compound-specific variable affinity for different transporters/receptors, their effect on preeclampsia risk could differ. Our study examined the risk of preeclampsia (and its subtypes) following exposure to different classes of antidepressants, also accounting for specific transporters/receptors targeted by antidepressants. MethodsWe conducted a cohort study, combining data from the Netherlands Perinatal Registry and the PHARMO Database Network. Exposure to antidepressants was examined from conception to week 20 of gestation; extended use thereafter was also studied. Antidepressants were categorized according to classes [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and according to target transporters/receptors. Women not using any antidepressants during 15 months before delivery were included as reference. ResultsWe included 2,103 exposed and 95,376 reference women. Preeclampsia occurred in 70 exposed women (15 early-onset, 55 late-onset) and in 2,582 reference women (387 early-onset, 2,195 late-onset). TCA monotherapy (214 women) was associated with an increased risk of preeclampsia (n = 15, RR 2.46, 95% CI 1.51–4.02) and late-onset preeclampsia (n = 12, RR 2.41, 95% CI 1.39–4.17, early-onset could not be evaluated). No association was detected with SSRIs, SNRIs and MAOIs. We did observe an increased risk of early-onset preeclampsia following exposure to 5-HT2A antagonizing antidepressants (6/405 women, excluding TCA users, RR 3.56, 95% CI 1.60–7.94). ConclusionsOur results support an increased risk of preeclampsia and the late-onset subtype among TCA users. The association between 5-HT2A antagonists and the early-onset subtype needs to be interpreted with caution based on the relatively small number of exposed cases.

A population-based linked cohort of cancer and primary care data: A new source to study the management of cancer in primary care.

ObjectiveInsight into the management of cancer in the primary care setting is pivotal to improve early recognition and survival of cancer patients. Therefore, the Netherlands Cancer Registry (NCR) was linked to the General Practitioner (GP) Database of the PHARMO Database Network to make this research possible.MethodsThe NCR collects tumour data on all newly diagnosed cancer patients, whereas the GP Database comprises data from electronic patient records registered by GPs. Databases were linked using a probabilistic record linkage technology.ResultsThrough record linkage of the NCR and the GP Database, we have established a large population‐based cohort (NCR‐PHARMO GP cohort) of 135,868 cancer patients. Data are available on demographics, tumour characteristics, primary health care use before and after cancer diagnosis including medication use, medical conditions, laboratory tests, and referrals. Data can be used for a number of different studies, for example, to study the diagnostic pathway in the primary care setting in order to identify possibilities for early recognition.ConclusionThe NCR‐PHARMO GP cohort provides rich data on the primary care management of cancer facilitating large‐scale observational cancer research in the primary care setting. The patient‐level linkage allows for long‐term follow‐up of cancer patients, with ongoing annual updates.

Use of potentially inappropriate medication in older patients with lung cancer at the end of life

ObjectivesMedications at the end of life should be used for symptom control. Medications which potential adverse effects outweigh their expected benefits are called ‘potentially inappropriate medications’ (PIMs). PIMs are related with adverse drug events and reduced quality of life. In this study, we investigated to what extent PIMs are dispensed to older patients with lung cancer in the last month of life. MethodsWe selected patients with lung cancer, aged 65+, diagnosed between 2009 and 2014, and who died before April 1st 2015 from the population-based Netherlands Cancer Registry (NCR). The NCR is linked to the PHARMO Database Network, that includes medications dispensed by community pharmacies in the Netherlands. The eight PIM groups were based on the OncPal Deprescribing Guideline: aspirin, dyslipidaemia medications, antihypertensives, osteoporosis medications, peptic ulcer prophylaxis, oral hypoglycaemics, vitamins and minerals. ResultsData of 7864 patients with lung cancer were analyzed. Median age was 74 year (IQR = 70–79) and 67% was male. 45% of all patients received at least one PIM in their last month of life. Taking into account all dispensed medications, patients receiving PIMs received more different medications compared to those receiving no PIMs, respectively 10 (SD = 5) vs. 3 (SD = 4) different medications (P < 0.001). ConclusionAlmost half of the older patients with lung cancer in the Netherlands received PIMs in their last month of life. Since PIM use is associated with reduced quality of life, it is important that health care professionals continue to critically assess which medication can be discontinued at the end of life.

Sex differences associated with adverse drug reactions resulting in hospital admissions

BackgroundAdverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5–1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission.MethodsADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged ≥ 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated.ResultsA total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men.ConclusionsThere are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics.

Impact of anticoagulant exposure misclassification on the bleeding risk of direct oral anticoagulants.

AimsDrug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not specialist). This study aims to quantify the impact of such exposure misclassification on the risk of major bleeding and stroke/transient ischaemic attack (TIA)associated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs).MethodsIncident anticoagulant users (>12 mo free of anticoagulation use) in the Dutch PHARMO Database Network between 2008 and 2017 were included. Drug exposure was assessed using pharmacy dispensing information. The risks of hospital admission of major bleeding for DOAC vs. VKA users was assessed with Cox regression analysis, where exposure was based on all dispensings, on general practitioner (GP)‐prescribed dispensings only or on specialist‐prescribed dispensings only. Hazard ratios (HRs) were estimated also for hospitalization for gastrointestinal bleeding, intracranial bleeding and stroke/TIA.ResultsWe included 99 182 VKA‐initiators and 21 795 DOAC‐initiators. Use of DOAC was associated with a lower risk of major bleeding compared to VKA use; HR 0.79 (95% confidence interval 0.70–0.90), 0.78 (0.68–0.91) and 0.62 (0.50–0.76), for exposure based on complete dispensing information, only GP‐ and only specialist‐prescribed dispensings, respectively. Similar results were found for the other bleeding outcomes. For stroke/TIA the HRs were 0.96 (0.84–1.09), 1.00 (0.84–1.18) and 0.72 (0.58–0.90), respectively.ConclusionIncluding only GP‐prescribed anticoagulant dispensings in this case did not materially impact the effect estimates compared to including all anticoagulant dispensings. Including only specialist‐prescribed dispensings, however, strengthened the effect estimates.

Respiratory morbidity, healthcare resource use, and cost burden associated with extremely preterm birth in The Netherlands

Background Extremely preterm (EP) infants have high rates of respiratory morbidity and correspondingly high healthcare resource utilization. Objectives Data from the PHARMO Perinatal Research Network were analyzed to quantify the burden of EP birth in the Netherlands. Methods A retrospective analysis included infants <28 weeks gestational age with a birth record in the Perinatal Registry (1999–2015) and data in the PHARMO Database Network. Outcomes of interest included select comorbidities, hospital readmissions, and costs of hospitalization and medication up to 1- and 2-years corrected age. Outcomes were stratified by birth period (1999–2005, 2000–2009, 2010–2015) and by diagnosis of bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD). Results The cohort included 168 EP infants (37 born 1999–2005, 51 born 2006–2009, 80 born 2010–2015). Median (Q1–Q3) birth weights decreased by birth period from 970 (840–1,035) g in 1999–2005 to 853 (695–983) g in 2010–2015. Overall, BPD and CLD were reported during the birth hospitalization in 40% and 29% of infants, respectively; rates of BPD increased and rates of CLD decreased by birth period. Eighty-four percent of EP infants had an additional comorbidity. Mean (standard deviation) costs of birth hospitalization were €110,600 (€73,000) for 1999–2005, €119,350 (€60,650) for 2006–2009, and €138,800 (€130,100) for 2010–2015. Birth hospitalization and total costs for up to 1- and 2-years corrected age were higher for infants with BPD and/or CLD than for those without either complication. Conclusion Healthcare resource utilization and costs for EP infants, especially for those with respiratory morbidities, increased between 1999 and 2015. Future cost-effectiveness analyses are essential to determine the economic impact of this change and underscore the need for new therapeutic interventions to decrease clinical sequelae in this vulnerable population.

Platelet aggregation inhibitor prescription for newly diagnosed peripheral arterial disease in the Netherlands: a cohort study

ObjectivesPharmacological treatment of peripheral arterial disease (PAD) comprises of antiplatelet therapy (APT), blood pressure control and cholesterol optimisation. Guidelines provide class-I recommendations on the prescription, but there are little data...

Heart failure medication after a first hospital admission and risk of heart failure readmission, focus on beta-blockers and renin-angiotensin-aldosterone system medication: A retrospective cohort study in linked databases.

This study assessed the association between heart failure (HF) medication (angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB), beta-blockers (BB), mineralocorticoid-receptor antagonists (MRA) and diuretics) and HF readmissions in a real-world unselected group of patients after a first hospital admission for HF. Furthermore we analysed readmission rates for ACEI versus ARB and for carvedilol versus β1-selective BB and we investigated the effect of HF medication in relation to time since discharge. Medication at discharge was determined with dispensing data from the Dutch PHARMO Database Network including 22,476 patients with HF between 2001 and 2015. After adjustment for age, gender, number of medications and year of admission no associations were found for users versus non-users of ACEI/ARB (hazard ratio, HR = 1.01; 95%CI 0.96-1.06), BB (HR = 1.00; 95%CI 0.95-1.05) and readmissions. The risk of readmission for patients prescribed MRA (HR = 1.11; 95%CI 1.05-1.16) or diuretics (HR = 1.17; 95%CI 1.09-1.25) was higher than for non-users. The HR for ARB relative to ACEI was 1.04 (95%CI 0.97-1.12) and for carvedilol relative to β1-selective BB 1.33 (95%CI 1.20-1.46). Post-hoc analyses showed a protective effect shortly after discharge for most medications. For example one month post discharge the HR for ACEI/ARB was 0.77 (95%CI 0.69-0.86). Although we did try to adjust for confounding by indication, probably residual confounding is still present. Patients who were prescribed carvedilol have a higher or at least a similar risk of HF readmission compared to β1-selective BB. This study showed that all groups of HF medication -some more pronounced than others- were more effective immediately following discharge.

CV4 Patients with Hypercholesterolaemia or MIXED Dyslipidaemia and High or VERY High Cardiovascular Risk According to ESC/EAS Guidelines – a Population-Based CROSS–Sectional Study from the Netherlands

To describe the proportion, clinical characteristics, treatment patterns and healthcare utilization of patients with hypercholesterolaemia/mixed dyslipidaemia and high or very high cardiovascular (CV) risk according to the 2016 ESC/EAS guidelines, in the Netherlands. The analysis was done using the PHARMO Database Network, which combines anonymous data linked on a patient level from different primary and secondary healthcare settings in Netherlands. A cross-sectional cohort was constructed, including patients with a diagnosis of hypercholesterolaemia/mixed dyslipidaemia or ever treated with lipid lowering treatment (LLT) in the period 2009-2018. Included were those that in 2018 were classified as high or very high CV risk based on the 2016 ESC/EAS guidelines or were classified as statin intolerant and had a recorded Low Density Lipoprotein-Cholesterol (LDL-C). We identified 173,321 patients with hypercholesterolaemia/mixed dyslipideamia based on a recorded diagnosis or a history of LLT, of which 54,346 met the inclusion criteria. Out of those, 30% were of high risk and 70% of very high CV risk. The mean age was 70.9 (standard deviation 10.3) and the proportion of female was 46%. 66% of the patients had an atherosclerotic CV disease, with myocardial infarction (25%) and angina pectoris (32%) being the most frequently recorded diagnoses. Documented statin intolerance was reported in 3% of the patients. Only 35% of the patients had an LDL-C <1.8 mmol/L (70 mg/dl), while 25% had an LDL-C >2.6 mmol/L (100 mg/dL). Statin alone is the most common LLT (93%) administered mostly at moderate intensity (73%). 5% of the patients received ezetimibe as monotherapy or with statins. Ongoing analysis will cover also the healthcare utilization. Despite current LLT, LDL-C levels remain high in patients who are at CV risk, suggesting that additional therapies and strategies are needed.

Prevalence and incidence rate of hospital admissions related to medication between 2008 and 2013 in The Netherlands.

PurposeIn 2009 a Dutch guideline was published containing recommendations to reduce Hospital Admissions Related to Medications (HARMs). This study aims to examine time‐trends of HARMs and their potential preventability between 2008 and 2013 in The Netherlands.MethodsA retrospective prevalence study was conducted using the Dutch PHARMO Database Network. A semi‐automated pre‐selection was used to make a crude identification of possible HARMs of which four samples were selected. These were independently assessed with respect to causality and potential preventability by a physician and pharmacist. The results were stratified by age into 18‐64 years and 65 years and older. For these groups the net prevalences and incidence rates of HARMs and potentially preventable HARMs were calculated for the years 2008, 2009, 2011 and 2013.ResultsFour samples of 467 (2008), 447 (2009), 446 (2011) and 408 (2013) admissions were assessed. The net prevalence of HARMs in the 18‐64 years group was approximately four times smaller compared to the older group with a mean prevalence of 2.7% (95% confidence interval [CI]:2.4%‐3.0%) and 10.2% (95%CI: 9.7%‐10.7%) respectively. The potential preventability was 25.1% (18.4%‐31.8%) and 48.3% (95%CI: 44.8%‐51.8%), respectively. The prevalence of HARMs in both groups did not change significantly between 2008 and 2013 with 2.4% (95%CI: 1.9%‐3.0%) and 10.0% (95%CI: 9.0%‐11.0%) in 2008 and 3.1% (2.7%‐3.5%) and 10.4% (95%CI: 9.4%‐11.4%) in 2013, respectively.ConclusionDespite efforts to reduce HARMs, the prevalence did not decrease over time. Additional measures are therefore necessary, especially in the elderly population.